In 2008, there were an estimated 12.7 million cases of cancer diagnosed worldwide and about 7.6 million deaths. The global cancer burden is growing at an alarming pace; in 2030 alone, about 21.3 million new cancer cases and 13.1 million cancer deaths are expected to occur, simply due to the growth and aging of the population. Cancer is the second most common cause of death in the US, exceeded only by heart disease, accounting for nearly 1 of every 4 deaths. The National Cancer Institute estimates that approximately 13.7 million Americans with a history of cancer were alive on Jan. 1, 2012. Some of these individuals were cancer free, while others still had evidence of cancer and may have been undergoing treatment. About 1,660,290 new cancer cases are expected to be diagnosed in the US in 2013. In 2013, about 580,350 Americans are expected to die of cancer, almost 1,600 people per day. Although medical advances have improved cancer survival rates, there is a continuing need for new and more effective treatment.
Cancer is characterized by uncontrolled cell reproduction. Mitosis is a stage in the cell cycle during which a series of complex events ensure the fidelity of chromosome separation into two daughter cells. Several current cancer therapies, including the taxanes and vinca alkaloids, act to inhibit the mitotic machinery. Mitotic progression is largely regulated by proteolysis and by phosphorylation events that are mediated by mitotic kinases. Aurora kinase family members (e.g., Aurora A, Aurora B) regulate mitotic progression through modulation of centrosome separation, spindle dynamics, spindle assembly checkpoint, chromosome alignment/segregation, and cytokinesis (Dutertre et al., Oncogene, 21: 6175 (2002); Berdnik et al., Curr. Biol., 12: 640 (2002)). Overexpression and/or amplification of Aurora kinases have been linked to oncogenesis in several tumor types including those of colon and breast (Warner et al., Mol. Cancer Ther., 2: 589 (2003); Bischoff et al., EMBO, 17: 3062 (1998); Sen et al., Cancer Res., 94: 1320 (2002)). Moreover, Aurora kinase inhibition in tumor cells results in mitotic arrest and apoptosis, suggesting that these kinases are important targets for cancer therapy (Manfredi et al., PNAS, 104: 4106 (2007); Ditchfield, J. Cell Biol., 161: 267 (2003); Harrington et al., Nature Med., 1 (2004)). Given the central role of mitosis in the progression of virtually all malignancies, inhibitors of the Aurora kinases are expected to have application across a broad range of human tumors.
CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker. This receptor is expressed by activated, but not by resting, T and B cells. It is a positive regulator of apoptosis, and also has been shown to limit the proliferative potential of autoreactive CD8 effector T cells and protect the body against autoimmunity CD30 is associated with various lymphomas. CD30 is associated with anaplastic large cell lymphoma. CD30 is also expressed on classical Hodgkin Lymphoma Reed-Sternberg cells. The U.S. Food and Drug Administration has approved the therapeutic use of a CD30-directed antibody-drug conjugate (ADC), brentuximab vedotin (ADCETRIS®), for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The European Medicines Agency has also conditionally approved brentuximab vedotin (ADCETRIS®) for i) the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma following autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option and ii) the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). The anti-tumor activity of brentuximab vedotin is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the release of the conjugated payload, namely monomethyl auristatin E (MMAE) via proteolytic cleavage
However, while anti-CD30 antibodies and, in particular, brentuximab vedotin, have been reported to be effective for treatment of lymphomas, such as non-Hodgkin's lymphoma, the treated patients may be subject to disease relapse. Therefore, it would be beneficial if alternative treatment regimens could be developed. Combined treatment regimens could be helpful for patients suffering from solid tumors or hematological malignancies, and might potentially even decrease the rate of relapse or overcome the resistance to a particular anticancer agent sometime seen in these patients. Additionally, combinations of anticancer agents may have additive, or even synergistic, therapeutic effects.
There is thus a need for new cancer treatment regimens, including combination therapies.